Novel and selective spiroindoline-based inhibitors of Sky kinase

Noel A Powell; Jeffrey T Kohrt; Kevin J Filipski; Michael Kaufman; Derek Sheehan; Jeremy E Edmunds; Amy Delaney; Yuli Wang; Francis Bourbonais; Doh-Yeel Lee; Frank Schwende; Fang Sun; Pat McConnell; Cornel Catana; Huifen Chen; Jeff Ohren; Lisa A Perrin

doi:10.1016/j.bmcl.2011.11.036

Novel and selective spiroindoline-based inhibitors of Sky kinase

Bioorg Med Chem Lett. 2012 Jan 1;22(1):190-3. doi: 10.1016/j.bmcl.2011.11.036. Epub 2011 Nov 16.

Authors

Noel A Powell¹, Jeffrey T Kohrt, Kevin J Filipski, Michael Kaufman, Derek Sheehan, Jeremy E Edmunds, Amy Delaney, Yuli Wang, Francis Bourbonais, Doh-Yeel Lee, Frank Schwende, Fang Sun, Pat McConnell, Cornel Catana, Huifen Chen, Jeff Ohren, Lisa A Perrin

Affiliation

¹ Pfizer Global Research & Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. napowell@comcast.net

PMID: 22119469
DOI: 10.1016/j.bmcl.2011.11.036

Abstract

We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.

MeSH terms

Absorption
Adenosine Triphosphate / chemistry
Administration, Oral
Animals
Binding Sites
Biological Availability
Chemistry, Pharmaceutical / methods*
Crystallography, X-Ray / methods
Drug Design
Humans
Inhibitory Concentration 50
Intestines / drug effects*
Models, Chemical
Platelet Aggregation
Rats
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / chemistry

Substances

Adenosine Triphosphate
Receptor Protein-Tyrosine Kinases
TYRO3 protein, human